EP3357514B1 - Dérivé de lipide dans lequel un polymère hydrophile est lié par l'intermédiaire de lieurs de benzylidène-acétal cyclique - Google Patents
Dérivé de lipide dans lequel un polymère hydrophile est lié par l'intermédiaire de lieurs de benzylidène-acétal cyclique Download PDFInfo
- Publication number
- EP3357514B1 EP3357514B1 EP16851783.7A EP16851783A EP3357514B1 EP 3357514 B1 EP3357514 B1 EP 3357514B1 EP 16851783 A EP16851783 A EP 16851783A EP 3357514 B1 EP3357514 B1 EP 3357514B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- group
- formula
- carbon atoms
- bond
- substituent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 150000002632 lipids Chemical class 0.000 title claims description 52
- 229920001477 hydrophilic polymer Polymers 0.000 title claims description 43
- 125000001424 substituent group Chemical group 0.000 claims description 84
- -1 acryl group Chemical group 0.000 claims description 68
- 125000004432 carbon atom Chemical group C* 0.000 claims description 66
- 125000000524 functional group Chemical group 0.000 claims description 55
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 35
- 125000002947 alkylene group Chemical group 0.000 claims description 31
- 239000002202 Polyethylene glycol Substances 0.000 claims description 27
- 229920001223 polyethylene glycol Polymers 0.000 claims description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 24
- 229910052799 carbon Inorganic materials 0.000 claims description 19
- 125000002252 acyl group Chemical group 0.000 claims description 13
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 13
- 125000003277 amino group Chemical group 0.000 claims description 11
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 claims description 11
- 125000003172 aldehyde group Chemical group 0.000 claims description 10
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 8
- 125000001153 fluoro group Chemical group F* 0.000 claims description 7
- 125000000304 alkynyl group Chemical group 0.000 claims description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide group Chemical group [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000004104 aryloxy group Chemical group 0.000 claims description 4
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims description 4
- 125000005587 carbonate group Chemical group 0.000 claims description 4
- AFOSIXZFDONLBT-UHFFFAOYSA-N divinyl sulfone Chemical group C=CS(=O)(=O)C=C AFOSIXZFDONLBT-UHFFFAOYSA-N 0.000 claims description 4
- 125000003700 epoxy group Chemical group 0.000 claims description 4
- 125000004185 ester group Chemical group 0.000 claims description 4
- IQPQWNKOIGAROB-UHFFFAOYSA-N isocyanate group Chemical group [N-]=C=O IQPQWNKOIGAROB-UHFFFAOYSA-N 0.000 claims description 4
- ZBKFYXZXZJPWNQ-UHFFFAOYSA-N isothiocyanate group Chemical group [N-]=C=S ZBKFYXZXZJPWNQ-UHFFFAOYSA-N 0.000 claims description 4
- 125000005439 maleimidyl group Chemical group C1(C=CC(N1*)=O)=O 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- 150000001340 alkali metals Chemical class 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000005414 dithiopyridyl group Chemical group 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 229920001515 polyalkylene glycol Polymers 0.000 claims description 3
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 3
- 229920000954 Polyglycolide Polymers 0.000 claims description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 2
- 125000004442 acylamino group Chemical group 0.000 claims description 2
- 125000004423 acyloxy group Chemical group 0.000 claims description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium group Chemical group [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 2
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 229920001577 copolymer Polymers 0.000 claims description 2
- 229920000765 poly(2-oxazolines) Polymers 0.000 claims description 2
- 229920000747 poly(lactic acid) Polymers 0.000 claims description 2
- 229920002401 polyacrylamide Polymers 0.000 claims description 2
- 229920000058 polyacrylate Polymers 0.000 claims description 2
- 229920000515 polycarbonate Polymers 0.000 claims description 2
- 239000004417 polycarbonate Substances 0.000 claims description 2
- 239000004633 polyglycolic acid Substances 0.000 claims description 2
- 239000004626 polylactic acid Substances 0.000 claims description 2
- 229920000642 polymer Polymers 0.000 claims description 2
- 229920000193 polymethacrylate Polymers 0.000 claims description 2
- 229920002635 polyurethane Polymers 0.000 claims description 2
- 239000004814 polyurethane Substances 0.000 claims description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 3
- 150000001875 compounds Chemical class 0.000 description 94
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 64
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 57
- 238000006243 chemical reaction Methods 0.000 description 56
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- 230000007062 hydrolysis Effects 0.000 description 42
- 238000006460 hydrolysis reaction Methods 0.000 description 42
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 39
- 238000005160 1H NMR spectroscopy Methods 0.000 description 38
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 37
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 35
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- 125000006239 protecting group Chemical group 0.000 description 29
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 27
- 101150065749 Churc1 gene Proteins 0.000 description 27
- 102100038239 Protein Churchill Human genes 0.000 description 27
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 27
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 23
- 239000000243 solution Substances 0.000 description 23
- 239000002904 solvent Substances 0.000 description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 22
- 239000000203 mixture Substances 0.000 description 21
- 230000002829 reductive effect Effects 0.000 description 21
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 20
- 229910052757 nitrogen Inorganic materials 0.000 description 19
- 238000001914 filtration Methods 0.000 description 18
- 150000002430 hydrocarbons Chemical group 0.000 description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 17
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 16
- 239000012528 membrane Substances 0.000 description 16
- 210000001519 tissue Anatomy 0.000 description 16
- 238000005259 measurement Methods 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 150000001555 benzenes Chemical class 0.000 description 14
- 238000005859 coupling reaction Methods 0.000 description 14
- 230000002378 acidificating effect Effects 0.000 description 13
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- 239000013078 crystal Substances 0.000 description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 12
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 11
- 150000007530 organic bases Chemical class 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- XSXHWVKGUXMUQE-UHFFFAOYSA-N osmium dioxide Inorganic materials O=[Os]=O XSXHWVKGUXMUQE-UHFFFAOYSA-N 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 9
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 9
- 239000000872 buffer Substances 0.000 description 9
- 238000002425 crystallisation Methods 0.000 description 9
- 230000008025 crystallization Effects 0.000 description 9
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 150000007529 inorganic bases Chemical class 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- HEVMDQBCAHEHDY-UHFFFAOYSA-N (Dimethoxymethyl)benzene Chemical compound COC(OC)C1=CC=CC=C1 HEVMDQBCAHEHDY-UHFFFAOYSA-N 0.000 description 7
- 125000006091 1,3-dioxolane group Chemical group 0.000 description 7
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 125000004429 atom Chemical group 0.000 description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 125000005647 linker group Chemical group 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- 229910052708 sodium Inorganic materials 0.000 description 7
- 125000006850 spacer group Chemical group 0.000 description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 125000004122 cyclic group Chemical group 0.000 description 6
- 238000010511 deprotection reaction Methods 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
- 229960002317 succinimide Drugs 0.000 description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- VDFVNEFVBPFDSB-UHFFFAOYSA-N 1,3-dioxane Chemical group C1COCOC1 VDFVNEFVBPFDSB-UHFFFAOYSA-N 0.000 description 5
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical group CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 5
- 0 CN(C(C=C1*)=O)C1=O Chemical compound CN(C(C=C1*)=O)C1=O 0.000 description 5
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 5
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 5
- 125000004036 acetal group Chemical group 0.000 description 5
- 150000001241 acetals Chemical group 0.000 description 5
- 239000000010 aprotic solvent Substances 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 5
- 230000004048 modification Effects 0.000 description 5
- 238000012986 modification Methods 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 238000004364 calculation method Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000010348 incorporation Methods 0.000 description 4
- 229910052700 potassium Inorganic materials 0.000 description 4
- 239000011591 potassium Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000001632 sodium acetate Substances 0.000 description 4
- 235000017281 sodium acetate Nutrition 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 239000008096 xylene Substances 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 238000006359 acetalization reaction Methods 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 125000001124 arachidoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 125000001204 arachidyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 238000010533 azeotropic distillation Methods 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- PFYXSUNOLOJMDX-UHFFFAOYSA-N bis(2,5-dioxopyrrolidin-1-yl) carbonate Chemical compound O=C1CCC(=O)N1OC(=O)ON1C(=O)CCC1=O PFYXSUNOLOJMDX-UHFFFAOYSA-N 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 210000001163 endosome Anatomy 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 150000007857 hydrazones Chemical class 0.000 description 3
- 230000003834 intracellular effect Effects 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 210000003712 lysosome Anatomy 0.000 description 3
- 230000001868 lysosomic effect Effects 0.000 description 3
- 125000001419 myristoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 108020004707 nucleic acids Proteins 0.000 description 3
- 150000007523 nucleic acids Chemical class 0.000 description 3
- 102000039446 nucleic acids Human genes 0.000 description 3
- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 3
- 150000003904 phospholipids Chemical class 0.000 description 3
- 125000005543 phthalimide group Chemical group 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 3
- BWKIBIZZLRPKFY-UHFFFAOYSA-N 1,2,3-benzothiadiazole-5-carbaldehyde Chemical compound O=CC1=CC=C2SN=NC2=C1 BWKIBIZZLRPKFY-UHFFFAOYSA-N 0.000 description 2
- ZWVMLYRJXORSEP-UHFFFAOYSA-N 1,2,6-Hexanetriol Chemical compound OCCCCC(O)CO ZWVMLYRJXORSEP-UHFFFAOYSA-N 0.000 description 2
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 2
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 2
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 description 2
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- WEVYAHXRMPXWCK-FIBGUPNXSA-N acetonitrile-d3 Chemical compound [2H]C([2H])([2H])C#N WEVYAHXRMPXWCK-FIBGUPNXSA-N 0.000 description 2
- 239000003377 acid catalyst Substances 0.000 description 2
- 239000003463 adsorbent Substances 0.000 description 2
- 125000005907 alkyl ester group Chemical group 0.000 description 2
- 125000004103 aminoalkyl group Chemical group 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 150000007514 bases Chemical class 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 150000001728 carbonyl compounds Chemical class 0.000 description 2
- 125000004181 carboxyalkyl group Chemical group 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 238000010531 catalytic reduction reaction Methods 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 125000003074 decanoyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C(*)=O 0.000 description 2
- 125000003493 decenyl group Chemical group [H]C([*])=C([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 125000005066 dodecenyl group Chemical group C(=CCCCCCCCCCC)* 0.000 description 2
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 125000003827 glycol group Chemical group 0.000 description 2
- 150000002334 glycols Chemical class 0.000 description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 230000036571 hydration Effects 0.000 description 2
- 238000006703 hydration reaction Methods 0.000 description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000003999 initiator Substances 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000000400 lauroyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 239000000693 micelle Substances 0.000 description 2
- 125000005064 octadecenyl group Chemical group C(=CCCCCCCCCCCCCCCCC)* 0.000 description 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 2
- 238000006116 polymerization reaction Methods 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 2
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 125000005063 tetradecenyl group Chemical group C(=CCCCCCCCCCCCC)* 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 description 1
- NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 description 1
- LVNGJLRDBYCPGB-LDLOPFEMSA-N (R)-1,2-distearoylphosphatidylethanolamine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[NH3+])OC(=O)CCCCCCCCCCCCCCCCC LVNGJLRDBYCPGB-LDLOPFEMSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- MWRBNPKJOOWZPW-NYVOMTAGSA-N 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine zwitterion Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP(O)(=O)OCCN)OC(=O)CCCCCCC\C=C/CCCCCCCC MWRBNPKJOOWZPW-NYVOMTAGSA-N 0.000 description 1
- 150000000180 1,2-diols Chemical group 0.000 description 1
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 description 1
- IAJHLVPJJCPWLF-UHFFFAOYSA-N 2,3-di(tetradecoxy)propan-1-ol Chemical compound CCCCCCCCCCCCCCOCC(CO)OCCCCCCCCCCCCCC IAJHLVPJJCPWLF-UHFFFAOYSA-N 0.000 description 1
- QEHCYTDFERPPPU-UHFFFAOYSA-N 2,3-dioctadecoxypropan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCOCC(CO)OCCCCCCCCCCCCCCCCCC QEHCYTDFERPPPU-UHFFFAOYSA-N 0.000 description 1
- SXGZJKUKBWWHRA-UHFFFAOYSA-N 2-(N-morpholiniumyl)ethanesulfonate Chemical compound [O-]S(=O)(=O)CC[NH+]1CCOCC1 SXGZJKUKBWWHRA-UHFFFAOYSA-N 0.000 description 1
- IUTPJBLLJJNPAJ-UHFFFAOYSA-N 3-(2,5-dioxopyrrol-1-yl)propanoic acid Chemical compound OC(=O)CCN1C(=O)C=CC1=O IUTPJBLLJJNPAJ-UHFFFAOYSA-N 0.000 description 1
- QSBHJTCAPWOIIE-UHFFFAOYSA-N 3-fluoro-4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1F QSBHJTCAPWOIIE-UHFFFAOYSA-N 0.000 description 1
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 1
- FZKLGTIIZCYUOM-UHFFFAOYSA-N CC1OC(c(cc2)cc(F)c2OC)OC1 Chemical compound CC1OC(c(cc2)cc(F)c2OC)OC1 FZKLGTIIZCYUOM-UHFFFAOYSA-N 0.000 description 1
- DTACWEXJFYOAKS-UHFFFAOYSA-N CC1OC(c(cc2)ccc2OC)OC1 Chemical compound CC1OC(c(cc2)ccc2OC)OC1 DTACWEXJFYOAKS-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 108020004459 Small interfering RNA Proteins 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- NUZWLKWWNNJHPT-UHFFFAOYSA-N anthralin Chemical compound C1C2=CC=CC(O)=C2C(=O)C2=C1C=CC=C2O NUZWLKWWNNJHPT-UHFFFAOYSA-N 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 125000003910 behenoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002511 behenyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 125000005998 bromoethyl group Chemical group 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- KFVUXNKQQOUCAH-UHFFFAOYSA-N butan-1-ol;propan-2-ol Chemical compound CC(C)O.CCCCO KFVUXNKQQOUCAH-UHFFFAOYSA-N 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 239000011903 deuterated solvents Substances 0.000 description 1
- XLYOFNOQVPJJNP-DYCDLGHISA-N deuterium hydrogen oxide Chemical compound [2H]O XLYOFNOQVPJJNP-DYCDLGHISA-N 0.000 description 1
- 229960002311 dithranol Drugs 0.000 description 1
- 125000006575 electron-withdrawing group Chemical group 0.000 description 1
- 230000004651 endocytosis pathway Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerol Substances OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 125000000755 henicosyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 125000000879 imine group Chemical group 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000002484 inorganic compounds Chemical class 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000010983 kinetics study Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 125000000628 margaroyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002960 margaryl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000006626 methoxycarbonylamino group Chemical group 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical compound CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 description 1
- 210000000865 mononuclear phagocyte system Anatomy 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000001196 nonadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001402 nonanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005187 nonenyl group Chemical group C(=CCCCCCCC)* 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002801 octanoyl group Chemical group C(CCCCCCC)(=O)* 0.000 description 1
- 125000004365 octenyl group Chemical group C(=CCCCCCC)* 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 125000002958 pentadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 125000001189 phytyl group Chemical group [H]C([*])([H])/C([H])=C(C([H])([H])[H])/C([H])([H])C([H])([H])C([H])([H])[C@@](C([H])([H])[H])([H])C([H])([H])C([H])([H])C([H])([H])[C@@](C([H])([H])[H])([H])C([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])C([H])([H])[H] 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 238000001226 reprecipitation Methods 0.000 description 1
- 125000001444 retinoyl group Chemical group O=C([*])/C([H])=C(C([H])([H])[H])/C([H])=C([H])/C([H])=C(C([H])([H])[H])/C([H])=C([H])/C1=C(C([H])([H])[H])C([H])([H])C([H])([H])C([H])([H])C1(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- UYCAUPASBSROMS-AWQJXPNKSA-M sodium;2,2,2-trifluoroacetate Chemical compound [Na+].[O-][13C](=O)[13C](F)(F)F UYCAUPASBSROMS-AWQJXPNKSA-M 0.000 description 1
- 238000000194 supercritical-fluid extraction Methods 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003613 toluenes Chemical class 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 125000005040 tridecenyl group Chemical group C(=CCCCCCCCCCCC)* 0.000 description 1
- 125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000297 undecanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005065 undecenyl group Chemical group C(=CCCCCCCCCC)* 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000008728 vascular permeability Effects 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
- C08G65/331—Polymers modified by chemical after-treatment with organic compounds containing oxygen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6905—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion
- A61K47/6907—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion the form being a microemulsion, nanoemulsion or micelle
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6905—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion
- A61K47/6911—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion the form being a liposome
- A61K47/6915—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion the form being a liposome the form being a liposome with polymerisable or polymerized bilayer-forming substances, e.g. polymersomes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/18—Radicals substituted by singly bound oxygen or sulfur atoms
- C07D317/20—Free hydroxyl or mercaptan
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/18—Radicals substituted by singly bound oxygen or sulfur atoms
- C07D317/22—Radicals substituted by singly bound oxygen or sulfur atoms etherified
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/18—Radicals substituted by singly bound oxygen or sulfur atoms
- C07D317/24—Radicals substituted by singly bound oxygen or sulfur atoms esterified
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/28—Radicals substituted by nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
- C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
- C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
- C08G65/33344—Polymers modified by chemical after-treatment with organic compounds containing nitrogen containing carbamate group
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
- C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
- C08G65/33396—Polymers modified by chemical after-treatment with organic compounds containing nitrogen having oxygen in addition to nitrogen
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
- C08G65/335—Polymers modified by chemical after-treatment with organic compounds containing phosphorus
- C08G65/3356—Polymers modified by chemical after-treatment with organic compounds containing phosphorus having nitrogen in addition to phosphorus
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G2650/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G2650/28—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule characterised by the polymer type
- C08G2650/58—Ethylene oxide or propylene oxide copolymers, e.g. pluronics
Definitions
- the present invention relates to a lipid derivative in which a hydrophilic polymer is bound through an acid-hydrolyzable acetal linker and which is used in surface modification of a carrier composed of a lipid membrane structure, for example, a liposome, a micelle, a vesicle or a lipid particle.
- a functional nucleic acid for example, siRNA, mRNA or antisense
- a protein exhibiting a physiological activity or a drug, for example, an anticancer drug
- the use of carrier has been investigated for the purpose of suppressing degradation due to an enzyme or the like in the living body or delivering the drug tissue-selectively.
- the functional nucleic acid or anticancer drug expresses the activity first after being incorporated into a cell
- the use of carrier is essential also in order to enhance the incorporation ability into the cell.
- a lipid membrane structure for example, a liposome, a micelle, a vesicle or a lipid fine particle, composed of a phospholipid, a cationic lipid or the like is particularly actively used.
- the lipid membrane structure Since the lipid membrane structure is recognized as a foreign matter by the living body, it is trapped by a reticuloendothelial system and discharged rapidly from blood.
- a technique for modifying a surface of the lipid membrane structure with a lipid derivative having bound a hydrophilic polymer of low antigenicity can prolong circulation time of the lipid membrane structure in blood.
- vascular permeability increases on the periphery of tumor tissue in comparison with a normal tissue, it is effective that the lipid membrane structure can be effectively integrated on the periphery of the tumor tissue by extending the circulation time in blood.
- a hydration layer formed by the hydrophilic polymer decreases the interaction with a cell membrane to inhibit in vivo/intracellular kinetics, for example, incorporation into the cell or endosomal escape.
- an approach to overcome by detaching the hydrophilic polymer from the lipid membrane structure in an appropriate timing has been made.
- Most of the strategies utilize an environmental change in each tissue of the living body, for example, reductive environment or the presence of absence of a specific enzyme, as a trigger of the detachment of hydrophilic polymer, and one of them is a technique of utilizing a change in pH.
- Non-Patent Document 1 a hydrazone linker is introduced between polyethylene glycol and a phospholipid. Moreover, although an attempt has been made to control the hydrolysis rate by controlling a number of carbon atoms of a spacer between the hydrazone linker and the phospholipid, a hydrolysis rate under an acid condition (pH 5.5) is constant regardless of the number of carbon atoms of a spacer and it is not possible to precisely control the hydrolysis rate.
- Non-Patent Document 2 kinetics study of the hydrolysis of hydrazone is described and it is shown that in the hydrolysis of hydrazone, the influence of differences in the substituents present on the neighboring benzene ring on the hydrolysis rate is small. Therefore, there is a possibility that the hydrazone is not the best choice for the purpose of controlling the hydrolysis rate.
- lipid derivatives each having an acid-hydrolyzable linker introduced into the structure for the purpose of detaching the hydrophilic polymer chain under the acidic environment in the living body
- lipid derivative in which a hydrophilic polymer is bound through an acid-hydrolyzable linker which is able to precisely control the hydrolysis rate at an arbitrary pH.
- Patent Document 1 WO2010/057150 A1
- the deviation of pH at each tissue of the living body is very small and, for example, although the periphery of a tumor tissue is an acidic environment in comparison with pH 7.4 in normal tissue, the pH thereof is weakly acidic of approximately from 6.4 to 6.9. Further, an endosomal interior is also week acidic of pH from 5.5 to 6.0. The endosomal interior is gradually acidified to approach pH 4.5 to 5.0 which is the pH of a lysosome. Since an endosome is finally fused with a lysosome, it is required that the drug or the like incorporated into the endosome should escape from the endosome at around pH 5.5 in order to avoid degradation thereof due to an enzyme in the lysosome.
- An object of the present invention is to provide a lipid derivative in which a hydrophilic polymer is bound through an acetal linker, and which can accurately control a hydrolysis rate at the pH of the weakly acidic environment in the living body to detach the hydrophilic polymer from a lipid membrane structure.
- the inventors have developed a lipid derivative in which a hydrophilic polymer is bound through a cyclic benzylidene acetal linker, and which can accurately control a hydrolysis rate at the pH of the weakly acidic environment in the living body.
- the feature of the invention resides in that a hydrophilic polymer and a lipid are bound through a cyclic benzylidene acetal linker having substituent(s).
- substituent(s) By appropriately selecting the kind and position of the substituent (s) on the benzene ring of the cyclic benzylidene acetal linker, the degrees of electron density and steric hindrance around the acetal group which affect the hydrolysis rate of the acetal linker can be adjusted.
- the invention relates to a lipid derivative in which a hydrophilic polymer is bound through a cyclic benzylidene acetal linker represented by formula (1).
- formula (1) the meaning of R 1 to R 7 , P, s, t, Z 1 and Z 2 is as defined in the claims.
- the hydrolysis rate of the cyclic benzylidene acetal linker can be controlled according to the pH of a weakly acidic environment in the living body and it is possible to selectively detach the hydrophilic polymer from the lipid membrane structure containing the lipid derivative as a constituting component at the pH of the target tissue.
- acetal as used in the specification means both of an acetal structure derived from an aldehyde and an acetal structure derived from a ketone, that is, a ketal structure.
- cyclic acetal as used in the invention means both of a 1,3-dioxolane structure of a 5-membered ring which is s is 1 and t is 0 in formula (1) and a 1,3-dioxane structure of a 6-membered ring which is s is 1 and t is 1 or s is 2 and t is 0 in formula (1)
- Each of R 1 and R 6 in formula (1) of the invention is a hydrogen atom or a hydrocarbon group, a number of carbon atoms of the hydrocarbon group is 10 or less, and specific examples of the hydrocarbon group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a tert-butyl group, a phenyl group and a benzyl group.
- a preferred embodiment of R 1 or R 6 is a hydrogen atom or a methyl group, and a hydrogen atom is more preferred.
- the benzene ring in formula (1) of the invention may have a plurality of substituents.
- substituents By appropriately selecting the kind, the position and the degree of electron-donating property and electron-withdrawing property of the substituents on the benzene ring, it is possible to adjust the degrees of electron density and steric hindrance around the acetal group which affects the hydrolysis rate of the cyclic acetal linker. This makes it possible to impart a desired hydrolysis rate to the cyclic acetal linker.
- the substituent on the benzene ring in formula (1) is described using the "substituent constant ( ⁇ )" which means the substituent constant in the Hammett's rule which quantifies the effect of the substituent on the reaction rate or equilibrium of benzene derivative.
- the Hammett's rule is applied only to a para-substituted or meta-substituted benzene derivative and cannot be applied to an ortho-substituted benzene derivative which is affected by steric hindrance. Therefore, in the case of ortho-substituted benzene derivative, the substituent constant means the substituent constant in the Taft's equation which extends the Hammett's rule described above.
- Equation (2) the Hammett's rule is represented by equation (2) shown below.
- log k / k 0 ⁇ (in the equation, k is a rate constant or equilibrium constant in an arbitrary reaction of a para-substituted or meta-substituted benzene derivative, k 0 is a rate constant or equilibrium constant in the case where the benzene derivative does not have a substituent, that is, the substituent is a hydrogen atom, ⁇ is a reaction constant, and ⁇ is a substituent constant.)
- the reaction constant ( ⁇ ) in equation (2) described above is a constant which is determined depending on reaction conditions, for example, the kind of reaction, temperature or solvent, and can be calculated from the slope of Hammett plots.
- the substituent constant ( ⁇ ) in equation (2) described above is a constant which is determined only depending on the kind and position of the substituent, regardless of the kind of reaction. In the case where no substituent is present, that is, the substituent is a hydrogen atom, the constant is "0".
- the term "electron-withdrawing” as used in the specification means the case where ⁇ is a positive value, and the term “electron-donating” means the case where ⁇ is a negative value.
- the Hammett's rule is applied only to para-substituted or meta-substituted benzene derivative and cannot be applied to the case of ortho-substituted benzene derivative which is affected by steric hindrance. Therefore, it is the Taft's equation that the effect of such steric hindrance is introduced as a factor of the position, that is, a position constant (Es) of the substituent, to extend the Hammett's rule so that it can also be applied to the case of the ortho-substituted benzene derivative.
- the Taft's equation is represented by equation (3) shown below.
- log k / k 0 ⁇ + Es (wherein k is a rate constant or equilibrium constant in an arbitrary reaction of para-substituted or meta-substituted benzene derivative, k 0 is a rate constant or equilibrium constant in the case where the benzene derivative does not have a substituent, that is, the substituent is a hydrogen atom, ⁇ * is a reaction constant, ⁇ * is a substituent constant, and Es is a position constant of the substituent.
- reaction constant ( ⁇ ) of para-substituted or meta-substituted benzene derivative and the reaction constant ( ⁇ *) of ortho-substituted benzene derivative are approximately equal, it is defined in the specification that ⁇ and ⁇ * are the same. Further, since the substituent constant ( ⁇ *) in the ortho position is similar to the substituent constant in the para position as described, for example, in “ Charton, M. Can. J. Chem. 1960, 38, 2493-2499 ", to the substituent constant in the ortho position in the specification is applied a corresponding substituent constant in the para position.
- the substituent constant ( ⁇ ) in the para position or the meta position is described in " Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165-195 ", and with respect to a substituent in which the substituent constant ( ⁇ ) is unknown the constant can be measured and determined by the method described in " Hammett, L. P. Chem. Rev. 1935, 17(1), 125-136 ".
- the position constant (Es) is described in “ Unger, S. H.; Hansch, C. Prog. Phys. Org. Chem. 1976, 12, 91-118 ".
- Es as used in the specification, a hydrogen atom is defined as "0".
- Z 1 is bound to the benzene ring of the cyclic benzylidene acetal and P-Z 1 is also a substituent of the benzene ring.
- the substituent constant of P-Z 1 can be determined by separately measuring the composition and polymerization degree of P and combination thereof with Z 1 , but, since the substituent constant of P-Z 1 is substantially affected largely by the structure in the vicinity of the binding portion to the benzene ring, the effect of the other portions is so small as to be ignored. Therefore, it is possible to use a known substituent constant of a structure similar to the structure in the vicinity of the binding portion to the benzene ring in place of separately measuring the substituent constant as to P-Z 1 .
- the substituent constant of P-Z 1 in the specification can be substituted with a substituent constant of a structure in which atom(s) bound to the third atom counted from the atom bound to the benzene ring of the backbone atoms of the main chain of P-Z 1 , excepting the second atom are substituted with hydrogen atom(s).
- the substituent constant of P-Z 1 can be substituted with a substituent constant of a structure in which the atom is substituted with a methyl group in place of a hydrogen atom.
- hydrolysis half-life (t 1/2 ) in a buffer at pH 5.5 and 37°C is preferably in the range from 5 minutes to 1 month, more preferably in the range from 5 minutes to 24 hours.
- t 1/2 hydrolysis half-life in a buffer at pH 5.5 and 37°C
- the substituent which can be used in the invention is a substituent which does not inhibit the reactions in the synthesis process of the lipid derivative.
- the substituent may be any of electron-withdrawing substituent and electron-donating substituent as far as it satisfies the condition described above, and the substituents may be used individually or in combination.
- the electron-withdrawing substituent is selected from the group consisting of an acyl group having from 2 to 5 carbon atoms, an alkoxycarbonyl group having from 2 to 5 carbon atoms, a carbamoyl group having from 2 to 5 carbon atoms, an acyloxy group having from 2 to 5 carbon atoms, an acylamino group having from 2 to 5 carbon atoms, an alkoxycarbonylamino group having from 2 to 5 carbon atoms, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an alkylsulfanyl group having from 1 to 4 carbon atoms, an alkylsulfonyl group having from 1 to 4 carbon atoms, an arylsulfonyl group having from 6
- the electron-donating substituent is selected from the group consisting of an alkyl group having from 1 to 4 carbon atoms and a ureido group having from 1 to 4 carbon atoms and, when in the para position or ortho position, an alkoxy group having from 1 to 4 carbon atoms, an aryl group having from 6 to 10 carbon atom and an aryloxy group having from 6 to 10 carbon atoms, and preferred examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a tert-butyl group and a ureido group.
- Preferred examples of the substituent which is an electron-withdrawing group in the meta position and an electron-donating group in the para position or ortho position include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a tert-butoxy group, a phenyl group and a phenoxy group.
- formula (1) includes a 1,3-dioxolane structure and at least one of R 2 and R 5 is a substituent other than a hydrogen atom
- the ranges of ⁇ in a buffer at pH 5.5 and 37°C at 5 minutes ⁇ t 1/2 ⁇ 24 hours and 5 minutes ⁇ t 1/2 ⁇ 1 month are calculated by using Taft's equation (3), respectively.
- formula (1) includes a 1,3-dioxolane structure and R 2 and R 5 are hydrogen atoms
- R 2 and R 5 are hydrogen atoms
- a preferred embodiment which satisfies -0.70 ⁇ ⁇ ⁇ 0.21 at the time of 5 minutes ⁇ t 1/2 ⁇ 24 hours is described below.
- the substituents shown herein means R 3 and R 4 and the structure used in place of P-Z 1 according to the definition described above.
- one of the para-positions in formula (1) is a methoxy group or an ethoxy group and at least one of the meta-positions is a methyl group, an ethyl group or a propyl group.
- the para position is an ethoxy group and both of the meta-positions are methyl groups.
- the para position in formula (1) is a methoxy group, an ethoxy group or an acetamide group. More preferably, the para position is an ethoxy group.
- the para position in formula (1) is a methoxy group, an ethoxy group or an acetamide group and at least one of the meta-positions is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. More preferably, the para position is an ethoxy group and one of the meta-positions is a fluorine atom.
- formula (1) includes a 1,3-dioxolane structure and at least one of R 2 and R 5 is a substituent other than a hydrogen atom
- R 2 and R 5 is a substituent other than a hydrogen atom
- a preferred embodiment which satisfies -2.11 ⁇ ⁇ ⁇ 0.04 at the time of 5 minutes ⁇ t 1/2 ⁇ 24 hours is described below.
- the substituents shown herein means R 3 and R 4 and the structure used in place of P-Z 1 according to the definition described above.
- the para position is an ethoxy group.
- both of R 2 and R 5 in formula (1) are methoxy groups
- the para position is an ethoxy group.
- the meta position is an ethoxy group or the para position is an acetamide group.
- the para position is an ethoxy group.
- one of R 2 and R 5 in formula (1) is a fluorine and the other is a hydrogen atom
- the para position is an ethoxy group or a ureido group.
- formula (1) includes a 1, 3-dioxane structure and R 2 and R 5 are hydrogen atoms
- t 1/2 of the hydrophilic polymer derivative is represented by 5 minutes ⁇ t 1/2 ⁇ 24 hours.
- the ranges of ⁇ at 5 minutes ⁇ t 1/2 ⁇ 1 month is calculated, it is found to be -0.41 ⁇ ⁇ ⁇ 0.41.
- formula (1) includes a 1,3-dioxane structure and at least one of R 2 and R 5 is a substituent other than a hydrogen atom
- the ranges of ⁇ in a buffer at pH 5.5 and 37°C at 5 minutes ⁇ t 1/2 ⁇ 24 hours and 5 minutes ⁇ t 1/2 ⁇ 1 month are calculated by using Taft's equation (3), respectively.
- the kind and position of the substituent (s) suitable for imparting the desired hydrolyzability to the hydrophilic polymer derivative having a cyclic benzylidene acetal linker of the invention can be reasonably set by performing the calculation described above using equation (2) and equation (3).
- Z 1 in formula (1) of the invention is a divalent spacer between the benzene ring of the cyclic benzylidene acetal group and the hydrophilic polymer
- Z 2 is a divalent spacer between the lipid and the cyclic benzylidene acetal group.
- These are independently an ether bond, an ester bond, a carbonate bond, an urethane bond, an amide bond, a secondary amino group, an alkylene group containing any of these bonds and group, a single bond or an alkylene group.
- the number of carbon atoms of the alkylene group is from 1 to 24.
- preferred examples of the alkylene group include structures such as (z1).
- Preferred examples of the alkylene group having an ether bond include structures such as (z2) or (z3).
- Preferred examples of the alkylene group having an ester bond include structures such as (z4).
- Preferred examples of the alkylene group having a carbonate bond include structures such as (z5).
- Preferred examples of the alkylene group having an urethane bond include structures such as (z6).
- Preferred examples of the alkylene group having an amide bond include structures such as (z7).
- Preferred examples of the alkylene group having a secondary amino group include structures such as (z8).
- p and q are each independently an integer of 1 to 12.
- a number of the structural units described above is 2 or less.
- P in formula (1) of the invention is a hydrophilic polymer selected from the group consisting of polyalkylene glycol, polyoxazoline, polycarbonate, polyurethane, polyvinyl alcohol, polyacrylate, polymethacrylate, polyacrylamide, polyvinylpyrrolidone, polylactic acid, polyglycolic acid, polyamino acid and copolymers derived from the polymers described above, and P is preferably polyalkylene glycol, and more preferably polyethylene glycol.
- polyethylene glycol as used in the specification means both of polyethylene glycol having a molecular weight distribution obtained by polymerization of ethylene oxide and a monodispersed polyethylene glycol obtained by binding of an oligoethylene glycol having a single molecular weight by a coupling reaction.
- P in formula (1) is a linear or branched polyethylene glycol.
- P in formula (1) is represented by formula (p1), formula (p2), formula (p3), formula (p4), formula (p5) or formula (p6).
- n is the number of repeating units per polyethylene glycol chain, and in the polyethylene glycol having a molecular weight distribution, it is defined that n is calculated by various theoretical calculations based on an average molecular weight of the compound.
- the range of n is from 3 to 1,000, preferably from 10 to 500, more preferably from 20 to 300, and most preferably from 40 to 150. Further, in formula (p2) and formula (p6), the range of n is from 3 to 500, preferably from 5 to 250, more preferably from 10 to 150, and most preferably from 20 to 80. Moreover, in formula (p3), formula (p4) and formula (p5), the range of n is from 3 to 400, preferably from 5 to 200, more preferably from 10 to 100, and most preferably from 20 to 80.
- m is a number of the methylene groups. Specifically, m is from 1 to 6, preferably from 3 to 5, and more preferably 4.
- X is a hydrocarbon group having from 1 to 7 carbon atoms or a chemically reactive functional group represented by formula (x1).
- Y-Z 3 - (x1) is a hydrocarbon group having from 1 to 7 carbon atoms or a chemically reactive functional group represented by formula (x1).
- hydrocarbon group having from 1 to 7 carbon atoms include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a hexyl group, a heptyl group, a phenyl group, a tolyl group and a benzyl group.
- the hydrocarbon group having from 1 to 7 carbon atoms is preferably a hydrocarbon group having from 1 to 3 carbon atoms, more preferably a methyl group or an ethyl group, and still more preferably a methyl group.
- Y is a chemically reactive functional group
- Z 3 is a divalent spacer between the functional group Y and the polyethylene glycol chain.
- the polyethylene glycol derivative can provide a lipid membrane structure having a target-directing property, for example, by binding a target-directing molecule to Y.
- Y is an active ester group of formula (a) shown below, an active carbonate group of formula (b) shown below, an aldehyde group, an isocyanate group, an isothiocyanate group, an epoxy group, a maleimide group, a vinyl sulfone group, an acryl group, a sulfonyloxy group, a carboxy group, a thiol group, a dithiopyridyl group, an ⁇ -haloacetyl group, an alkynyl group, an allyl group, a vinyl group, an amino group, an oxyamino group, a hydrazide group or an azide group.
- the functional group capable of forming a covalent bond upon a reaction with an amino group of the biofunctional molecule is an active ester group, an active carbonate group, an aldehyde group, an isocyanate group, an isothiocyanate group, an epoxy group, a maleimide group, a vinyl sulfone group, an acryl group, a sulfonyloxy group or a carboxy group
- the functional group capable of forming a covalent bond upon a reaction with a thiol group of the biofunctional molecule is an active ester group, an active carbonate group, an aldehyde group, an isocyanate group, an isothiocyanate group, an epoxy group, a maleimide group, a vinyl sulfone group, an acryl group, a sulfonyloxy group, a carboxy group, a thiol group, a dithiopyridyl group, an ⁇ -haloacetyl group, an al
- Y is a group represented by group (I), group (II), group (III), group (IV) or group (V) .
- R 10 is a hydrogen atom or a sulfo group, specific examples of the sulfo group include sodium sulfonate and potassium sulfonate, and R 10 is preferably a hydrogen atom.
- R 11 and R 14 are each a hydrogen atom or a hydrocarbon group having from 1 to 5 carbon atoms, and specific examples of the hydrocarbon group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a tert-butyl group and a pentyl group.
- R 12 is a hydrocarbon group having from 1 to 10 carbon atoms which may contain a halogen atom, specific examples of the hydrocarbon group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a hexyl group, a benzyl group, a 4-methylphenyl group, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, a 4- (trifluoromethoxy) phenyl group, a vinyl group, a chloroethyl group, a bromoethyl group and an iodoethyl group, and R 12 is preferably a methyl group, a vinyl group, a 4-methylphenyl group or a 2,2,2-trifluoroethyl group.
- R 13 is a hal
- Z 3 is an ether bond, an ester bond, a carbonate bond, an urethane bond, an amide bond, a secondary amino group, an alkylene group containing any of these bonds and group, a single bond or an alkylene group.
- the number of carbon atoms of the alkylene group is from 1 to 24.
- preferred examples of the alkylene group include structures such as (z1).
- Preferred examples of the alkylene group having an ether bond include structures such as (z2) or (z3).
- Preferred examples of the alkylene group having an ester bond include structures such as (z4).
- Preferred examples of the alkylene group having a carbonate bond include structures such as (z5).
- Preferred examples of the alkylene group having an urethane bond include structures such as (z6).
- Preferred examples of the alkylene group having an amide bond include structures such as (z7).
- Preferred examples of the alkylene group having a secondary amino group include structures such as (z8).
- p and q are each independently an integer of 1 to 12.
- p and q are preferably large, and when it is intended to be bound in a hydrophilic environment, p and q are preferably small.
- Z 3 is an ether bond, an ester bond, a carbonate bond, an urethane bond, an amide bond, a secondary amino group or an alkylene group containing any of these bonds and group and a plurality of identical structural units are bound, a number of the structural units described above is 2 or less.
- R 7 in formula (1) of the invention is represented by formula (A) or formula (B).
- R 8 and R 9 are each independently a hydrocarbon group having from 8 to 24 carbon atoms or an acyl group having from 8 to 24 carbon atoms.
- the hydrocarbon group having from 8 to 24 carbon atoms may be linear or branched and may contain an unsaturated bond.
- hydrocarbon group examples include an octyl group, a nonyl group, a decyl group, an undecyl group, a dodecyl group, a tridecyl group, a tetradecyl group, a pentadecyl group, a hexadecyl group, a heptadecyl group, an octadecyl group, a nonadecyl group, an eicosyl group, a heneicosyl group, a docosyl group, an octenyl group, a nonenyl group, a decenyl group, an undecenyl group, a dodecenyl group, a tridecenyl group, a tetradecenyl group, a pentadecenyl group, a hexadecenyl group, a heptadecenyl group, an
- the hydrocarbon group is preferably an aliphatic hydrocarbon group having from 10 to 20 carbon atoms, for example, a decyl group, a dodecyl group, a tetradecyl group, a hexadecyl group, an octadecyl group, an eicosyl group, a decenyl group, a dodecenyl group, a tetradecenyl group, a hexadecenyl group, an octadecenyl group, an eicosenyl group, a decadienyl group, a dodecadienyl group, a tetradecadienyl group, a hexadecadienyl group, an octadecadienyl group or an eicosadienyl group, and more preferably a hydrocarbon group having from 14 to 20 carbon atoms, for example, a
- the acyl group having from 8 to 24 carbon atoms for R 8 or R 9 may be linear or branched and may contain an unsaturated bond.
- Specific examples of the acyl group include an octanoyl group, a nonanoyl group, a decanoyl group, an undecanoyl group, a dodecanoyl group, a tridecanoyl group, a tetradecanoyl group, a pentadecanoyl group, a hexadecanoyl group, a heptadecanoyl group, an octadecanoyl group, a nonadecanoyl group, an eicosanoyl group, a heneicosanoyl group, a docosanoyl group, an octaenoyl group, a nonaenoyl group, a decaenoyl group, an undecaenoyl group,
- the acyl group is preferably an acyl group having from 10 to 20 carbon atoms, for example, a decanoyl group, a dodecanoyl group, a tetradecanoyl group, a hexadecanoyl group, an octadecanoyl group, an eicosanoyl group, a decaenoyl group, a dodecaenoyl group, a tetradecaenoyl group, a hexadecaenoyl group, an octadecaenoyl group, an eicosaenoyl group, a decadienoyl group, a dodecadienoyl group, a tetradecadienoyl group, a hexadecadienoyl group, an octadecadienoyl group or an eicosadienoyl group, and more preferably an
- M is a hydrogen atom, an alkali metal or an ammonium group.
- the alkali metal includes, for example, lithium, sodium or potassium, and is preferably sodium or potassium, and more preferably sodium.
- the lipid derivative in which a hydrophilic polymer is bound through a cyclic benzylidene acetal linker of the invention can be synthesized by performing a coupling reaction between a cyclic benzylidene acetal linker compound and a hydrophilic polymer derivative and then performing a coupling reaction between the hydrophilic polymer derivative having the cyclic benzylidene acetal linker and a lipid, or by performing a coupling reaction between a cyclic benzylidene acetal linker compound and a lipid and then performing a coupling reaction between the lipid derivative having the cyclic benzylidene acetal linker and a hydrophilic polymer derivative.
- the bond generated by the coupling reaction is determined by a combination of the functional groups used in the reaction.
- R 1 is a hydrogen atom or a hydrocarbon group
- R 2 , R 3 , R 4 and R 5 are each independently an electron-withdrawing or electron-donating substituent or a hydrogen atom.
- a carbonyl compound of formula (9) having a hydroxy group which is a chemically reactive functional group is allowed to react with a 1,2-diol derivative of formula (10) having a phthalimide group in which an amino group is protected with a phthaloyl group in an aprotic solvent, for example, toluene, benzene, xylene, acetonitrile, ethyl acetate, diethyl ether, tert-butyl methyl ether, tetrahydrofuran, chloroform, dichloromethane, dimethyl sulfoxide, dimethylformamide or dimethylacetamide or with no solvent in the presence of an acid catalyst to obtain a compound of formula (11) shown below having a cyclic benzylidene acetal group.
- an aprotic solvent for example, toluene, benzene, xylene, acetonitrile, ethyl acetate, diethyl ether,
- the resulting compound may be purified by extraction, recrystallization, adsorbent treatment, column chromatography or the like.
- a corresponding acetal derivative of a lower alcohol is preferably an alcohol having from 1 to 5 carbon atoms, and more preferably methanol or ethanol.
- the acid catalyst may be either an organic acid or an inorganic acid and is not particularly limited, and specific examples thereof include p-toluenesulfonic acid, pyridinium p-toluenesulfonate, methanesulfonic acid, 10-camphorsulfonic acid, hydrogen chloride, iodine, ammonium chloride, oxalic acid, boron trifluoride-diethyl ether complex and the like.
- the "protective group” as referred to herein is a component which prevents or blocks a reaction of a specific chemically reactive functional group in a molecule under certain reaction conditions.
- the protective group varies depending on the kind of the chemically reactive functional group to be protected, the conditions to be used and the presence of the other functional group or protective group in the molecule. Specific examples of the protective group can be found in many general books and are described, for example, in “ Wuts, P. G. M. ; Greene, T. W., Protective Groups in Organic Synthesis, 4th ed.; Wiley-Interscience: New York, 2007 ".
- the functional group protected by the protective group can be reproduce the original functional group by deprotection using reaction conditions suitable for each of the protective groups, that is, causing a chemical reaction. Therefore, in the specification, a functional group which is protected by a protective group and is capable of being deprotected by various reactions is included in the "chemically reactive functional group".
- the typical deprotection conditions of the protective group are described in the literature described above.
- a functional group other than the hydroxy group can also be used. Specific examples thereof include a hydroxyalkyl group, an amino group, an aminoalkyl group, a carboxy group and a carboxyalkyl group.
- the functional group described above may be protected by a protective group which is stable in the acidic conditions of the acetalization reaction and can be deprotected under reaction conditions other than catalytic reduction by which the cyclic benzylidene acetal group is decomposed.
- the functional group to be protected when the functional group to be protected is a hydroxy group or a hydroxyalkyl group, for example, a silyl protective group and an acyl protective group are exemplified, and specific examples thereof include a tert-butyldiphenylsilyl group, a tert-butyldimethylsilyl group, a triisopropylsilyl group, an acetyl group and a pivaloyl group.
- the functional group to be protected is an amino group or an aminoalkyl group
- an acyl protective group and a carbamate protective group are exemplified, and specific examples thereof include a trifluoroacetyl group, a 9-fluorenylmethyloxycarbonyl group and a 2- (trimethylsilyl) ethyloxycarbonyl group.
- the functional group to be protected is a carboxy group or a carboxyalkyl group
- an alkyl ester protective group and a silyl ester protective group are exemplified, and specific examples thereof include a methyl group, a 9-fluorenylmethyl group and a tert-butyldimethylsilyl group.
- the kinds and the typical deprotection conditions of the specific protective groups are described in the literature described above, and the reaction conditions suitable for each of the protective groups are selected and the deprotection can be performed before the reaction with the hydrophilic polymer intermediate.
- the chemically reactive functional group excepting the 1,2-diol moiety in the compound of formula (10) a functional group other than the phthalimide group can also be used.
- the chemically reactive functional group is a functional group which is protected by a protective group, it is necessary that the protective group is stable in the acidic conditions of the acetalization reaction and can be deprotected under reaction conditions other than catalytic reduction by which the benzylidene acetal group is decomposed.
- the functional group to be protected when the functional group to be protected is an amino group, for example, an acyl protective group and a carbamate protective group are exemplified, and specific examples thereof include a trifluoroacetyl group, a 9-fluorenylmethyloxycarbonyl group and a 2-(trimethylsilyl)ethyloxycarbonyl group.
- the functional group to be protected is a hydroxy group
- a silyl protective group and an acyl protective group are exemplified, and specific examples thereof include a tert-butyldiphenylsilyl group, a tert-butyldimethylsilyl group, a triisopropylsilyl group, an acetyl group and a pivaloyl group.
- the functional group to be protected is a carboxy group
- an alkyl ester protective group and a silyl ester protective group are exemplified, and specific examples thereof include a methyl group, a 9-fluorenylmethyl group and a tert-butyldimethylsilyl group.
- the functional group to be protected is a sulfanyl group
- a thioether protective group, a thiocarbonate protective group and a disulfide protective group are exemplified, and specific examples thereof include an S-2, 4-dinitrophenyl group, an S-9-fluorenylmethyloxycarbonyl group and an S-tert-butyldisulfide group.
- the typical deprotection conditions of the protective group are described in the literature described above, and the reaction conditions suitable for each of the protective groups are selected.
- the chemically reactive functional group is a functional group which does not inhibit the acetalization reaction even when it is not protected by a protective group, it is not necessary to use a protective group.
- Ethylene oxide is polymerized in an amount of 3 to 1,000 molar equivalents to methanol, which is an initiator, in toluene or with no solvent under alkaline conditions, for example, metallic sodium, metallic potassium, sodium hydride or potassium hydride to obtain polyethylene glycol of formula (12).
- the initiator is preferably an alcohol having a hydrocarbon group having from 1 to 24 carbon atoms, and specifically includes, for example, methanol, ethanol, propanol, isopropanol butanol, tert-butanol, phenol and benzyl alcohol. Since the polyethylene glycol has a hydroxy group which is a chemically reactive functional group, it can also be used as it is in a coupling reaction with a cyclic benzylidene acetal linker compound. CH 3 -(OCH 2 CH 2 ) n -OH ( 12 )
- the polyethylene glycol of formula (12) is allowed to react with methanesulfonyl chloride in an aprotic solvent, for example, toluene, benzene, xylene, acetonitrile, ethyl acetate, diethyl ether, tert-butyl methyl ether, tetrahydrofuran, chloroform, dichloromethane, dimethyl sulfoxide, dimethylformamide or dimethylacetamide or with no solvent in the presence of an organic base, for example, triethylamine, N-methylmorpholine, pyridine or 4-dimethylaminopyridine or an inorganic base, for example, sodium carbonate, sodium hydrogen carbonate, sodium acetate or potassium carbonate to obtain a polyethylene glycol intermediate of formula (13).
- an organic base for example, triethylamine, N-methylmorpholine, pyridine or 4-dimethylaminopyridine or an inorganic base, for example, sodium carbon
- the organic base and inorganic base may not be used.
- the use ratio of the organic base or the inorganic base is not particularly limited, and is preferably equimolar or more to the hydroxyl group of the polyethylene glycol of formula (12).
- the compound obtained may be purified by a purification means, for example, extraction, recrystallization, adsorbent treatment, reprecipitation, column chromatography or supercritical extraction.
- the chemically reactive functional group in the polyethylene glycol intermediate of formula (13) other functional groups can be also used.
- Preferred examples of the chemically reactive functional group are functional groups wherein the bond generated by the coupling reaction of the polyethylene glycol intermediate with the cyclic benzylidene acetal linker compound described above becomes the ether bond, the ester bond, the carbonate bond, the urethane bond, the amide bond, the secondary amino group, the alkylene group containing any of these bonds and group, the single bond or the alkylene group contained in the divalent spacer Z 1 of formula (1), and specifically include, for example, a halogen atom, an active ester, an active carbonate, an aldehyde group, an amino group, a hydroxy group and a carboxy group.
- the benzylidene acetal linker compound of formula (11) and the polyethylene glycol intermediate of formula (13) are subjected to a coupling reaction in an aprotic solvent, for example, toluene, benzene, xylene, acetonitrile, ethyl acetate, diethyl ether, tert-butyl methyl ether, tetrahydrofuran, chloroform, dichloromethane, dimethyl sulfoxide, dimethylformamide or dimethylacetamide or with no solvent in the presence of an organic base, for example, triethylamine, N-methylmorpholine, potassium tert-butoxide or sodium hexamethyldisilazane or an inorganic base, for example, potassium carbonate, potassium hydroxide or sodium hydride to obtain a compound of formula (14).
- an organic base for example, triethylamine, N-methylmorpholine, potassium tert-butoxide or sodium he
- the use ratio of the organic base or the inorganic base is not particularly limited, and is preferably equimolar or more to the chemically reactive functional group of the polyethylene glycol intermediate of formula (13). Also, it is possible to use the organic base as a solvent.
- the compound obtained may be purified by the purification means described above.
- the chemically reactive functional group of the cyclic benzylidene acetal linker compound may be subjected to functional group conversion before the coupling reaction with the polyethylene glycol intermediate.
- the reaction conditions for the coupling reaction are determined depending on the combination of the chemically reactive functional group of the cyclic benzylidene acetal linker compound and the chemically reactive functional group of the polyethylene glycol intermediate and a conventionally known method can be used. However, it is necessary to appropriately select conditions which do not decompose the bonds contained in the cyclic benzylidene acetal group and the divalent spacers Z 1 and Z 2 described above of formula (1).
- the compound of formula (14) is treated by using a basic organic compound, for example, ethylenediamine, methyl hydrazine or methylamine or a basic inorganic compound, for example, hydrazine, hydroxylamine or sodium hydroxide in a protic solvent, for example, water, methanol or ethanol, in an aprotic solvent, for example, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide or dimethylacetamide or with no solvent to obtain a compound of formula (15) in which the phthalimide group is deprotected and converted into an amino group.
- a basic organic compound for example, ethylenediamine, methyl hydrazine or methylamine or a basic inorganic compound, for example, hydrazine, hydroxylamine or sodium hydroxide
- a protic solvent for example, water, methanol or ethanol
- an aprotic solvent for example, acetonitrile, tetra
- the use ratio of the basic compound is not particularly limited, and is preferably equimolar or more to the chemically reactive functional group of the compound of formula (14). Also, it is possible to use the basic compound as a solvent.
- the compound obtained may be purified by the purification means described above.
- the compound of formula (15) is allowed to react with 1,2-dialkyl-3-(N-succinimidyl carboxy)-glycerol in an aprotic solvent, for example, toluene, benzene, xylene, acetonitrile, ethyl acetate, diethyl ether, tert-butyl methyl ether, tetrahydrofuran, chloroform, dichloromethane, dimethyl sulfoxide, dimethylformamide or dimethylacetamide or with no solvent in the presence of an organic base, for example, triethylamine, N-methylmorpholine, pyridine or 4-dimethylaminopyridine or an inorganic base, for example, sodium carbonate, sodium hydrogen carbonate, sodium acetate or potassium carbonate to obtain a compound of formula (16).
- an organic base for example, triethylamine, N-methylmorpholine, pyridine or 4-dimethylaminopyridine or an inorganic base
- the organic base and inorganic base may not be used.
- the use ratio of the organic base or the inorganic base is not particularly limited, and is preferably equimolar or more to the chemically reactive functional group of the compound of formula (15). Also, it is possible to use the organic base as a solvent.
- the compound obtained may be purified by the purification means described above.
- JNM-ECP400 or JNM-ECA600 produced by JEOL DATUM Ltd. was used.
- a tube of 5 mm ⁇ was used, and tetramethylsilane (TMS) was used as an internal standard substance in the case where a deuterated solvent was CDCl 3 , CD 3 CN or CD 3 OD, or HDO was used as a standard in the case of D 2 O.
- TMS tetramethylsilane
- TOF-MS In the measurement of an average molecular weight by TOF-MS, TOF-MS (Autoflex III produced by Bruker Inc.) was used, dithranol or 2,5-dihydroxybenzoic acid was used as a matrix, and sodium trifluoroacetate was used as a salt. In the analysis, Flex analysis was used, and molecular weight distribution analysis was conducted by Polytools. The number average molecular weight (Mn) obtained was described as the value of average molecular weight.
- a hydrolysis rate was evaluated by 1 H-NMR and calculated according to the calculation equation shown below by taking an integrated value of the hydrogen of the acetal group and an integral value of the hydrogen of the aldehyde group to be formed by hydrolysis as I 1 and I 2 , respectively.
- Hydrolysis rate % I 2 / I 1 + I 2 ⁇ 100
- Triethylamine (199 mg, 1.97 mmol) was added thereto and after stirring for a while, the solvent was distilled off under a reduced pressure. The residue was dissolved in chloroform, the solution was washed in order with an aqueous 20% by weight sodium chloride solution and ion-exchanged water, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under a reduced pressure to obtain a compound of formula (21).
- N,N'-disuccinimidyl carbonate 786 mg, 3.068 mmol
- dichloromethane 5.00 g
- the mixture was stirred at 20°C.
- a solution prepared by dissolving 1,2-dimyristyl glycerol (1.00 g, 2.046 mmol) and triethylamine (414 mg, 4.091 mmol) in dichloromethane (5.00 g) was dropwise added. After stirring for 4 hours, the deposits were filtered, and the filtrate was concentrated.
- Triethylamine (20.2 mg, 0.200 mmol) was added thereto and after stirring for a while, the mixture was washed with an aqueous 10% by weight sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, and after filtration, the solvent was distilled off under a reduced pressure to obtain a compound of formula (28) .
- a compound of formula (30) was obtained in the same manner as in Example 7.
- a compound of formula (34) was obtained in the same manner as in Examples 1 to 4.
- 1 H-NMR (CDCl 3 , internal standard TMS); ⁇ (ppm): 1.89 (2H, m, -C H 2 CH 2 -phthalimide), 3.19 (1H, m, -OCH 2 C H ⁇ ), 3.50-4.28 (6H, m, -OC H 2 C H ⁇ , -C H 2 CH 2 C H 2 -phthalimide), 7.70-7.86 (4H, m, -phthalimide)
- a compound of formula (35) was obtained in the same manner as in Examples 5 to 8.
- 1 H-NMR (CDCl 3 , internal standard TMS); ⁇ (ppm): 1.89 (2H, m, -C H 2 CH 2 -phthalimide), 3.19 (1H, m, -OCH 2 C H ⁇ ), 3.38 (3H, s, C H 3 O-), 3.52-4.41 (185H, m, -(OC H 2 C H 2 ) n -, -OC H 2 C H ⁇ , -C H 2 CH 2 C H 2 -phthalimide), 5.34 (0.8H, s, >C H -), 5.42 (0.2H, s, >C H -), 6.95-7.25 (3H, m, arom. H), 7.70-7.86 (4H, m, -phthalimide)
- a compound of formula (36) was obtained in the same manner as in Examples 9 to 11.
- a compound of formula (37) was obtained in the same manner as in Examples 12 to 15.
- 1 H-NMR (CDCl 3 , internal standard TMS); ⁇ (ppm): 1.89 (2H, m, -C H 2 CH 2 -OH), 3.19 (1H, m, -OCH 2 C H ⁇ ), 3.38 (3H, s, C H 3 O-), 3.52-4.41 (457H, m, -(OC H 2 C H 2 ) n -, -OC H 2 C H ⁇ , -C H 2 CH 2 C H 2 -OH), 5.61 (0.8H, s, >C H -), 5.68 (0.2H, s, >C H -), 6.78-7.40 (3H, m, arom. H)
- a compound of formula (38) was obtained in the same manner as in Examples 16 and 17.
- a compound of formula (40) was obtained by removing the tert-butyl group using hydrochloric acid from the compound of formula (39) synthesized according to the method described in JP-A-2010-248504 .
- 1 H-NMR (D 2 O, internal standard TMS); ⁇ (ppm): 3.14 (2H, t, -C H 2 NH 2 ), 3.40-4.00 (180H, m, -(OC H 2 C H 2 ) n -) H 2 N-(CH 2 ) 2 -(OCH 2 CH 2 ) n -OH (40) n about 45
- 1,2-Distearyl glycerol was allowed to react with phthalimide in the presence of diisopropyl azodicarboxylate and triphenylphosphine and then treated with ethylenediamine monohydrate to obtain a compound of formula (45).
- the compound of formula (46) was allowed to react in a 1M aqueous potassium carbonate solution at 25°C for 2 hours to perform deprotection of the trifluoroacetyl group, and then allowed to react with 3-maleimidopropionic acid N-succinimidyl in toluene to obtain a compound of formula (47).
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Polymers & Plastics (AREA)
- Dispersion Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Inorganic Chemistry (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Nanotechnology (AREA)
- Polyethers (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicinal Preparation (AREA)
Claims (8)
- Dérivé de lipide dans lequel un polymère hydrophile est lié par l'intermédiaire d'un lieur de benzylidène-acétal cyclique représenté par la formule (1) :
- Dérivé de lipide selon la revendication 1, dans lequel s vaut 1 et t vaut 0, R2 et R5 sont chacun un atome d'hydrogène, et une somme (Σσ) de constantes de substituants (σ) dans R3, R4 et P-Z1 satisfait -0,70 ≤ Σσ ≤ 0,76, dans lequel la constante de substituant (σ) est la constante de substituant selon l'équation de Hammett.
- Dérivé de lipide selon la revendication 1, dans lequel s vaut 1 et t vaut 0, au moins un de R2 et R5 est le substituant décrit ci-dessus, et une somme (Σσ) de constantes de substituants (σ) dans R3, R4 et P-Z1 satisfait -2,11 ≤ Σσ ≤ 0,59, dans lequel la constante de substituant (σ) est la constante de substituant selon l'équation de Hammett.
- Dérivé de lipide selon la revendication 1, dans lequel s vaut 1 et t vaut 1, ou s vaut 2 et t vaut 0, R2 et R5 sont chacun un atome d'hydrogène, et une somme (Σσ) de constantes de substituants (σ) dans R3, R4 et P-Z1 satisfait -0,41 ≤ Σσ ≤ 0,41, dans lequel la constante de substituant (σ) est la constante de substituant selon l'équation de Hammett.
- Dérivé de lipide selon la revendication 1, dans lequel s vaut 1 et t vaut 1, ou s vaut 2 et t vaut 0, au moins un de R2 et R5 est le substituant décrit ci-dessus, et une somme (Σσ) de constantes de substituants (σ) dans R3, R4 et P-Z1 satisfait -1,21 ≤ Σσ ≤ 0,31, dans lequel la constante de substituant (σ) est la constante de substituant selon l'équation de Hammett.
- Dérivé de lipide selon l'une quelconque des revendications 1 à 5, dans lequel Z1 et Z2 sont chacun indépendamment une liaison éther, une liaison ester, une liaison carbonate, une liaison uréthane, une liaison amide, un groupe amino secondaire, un groupe alkylène présentant 1 à 24 atomes de carbone et contenant l'un quelconque de ces liaisons et groupe, une liaison simple ou un groupe alkylène présentant 1 à 24 atomes de carbone et, dans un cas où au moins un de Z1 et Z2 est une liaison éther, une liaison ester, une liaison carbonate, une liaison uréthane, une liaison amide, un groupe amino secondaire ou un groupe alkylène présentant 1 à 24 atomes de carbone et contenant l'un quelconque de ces liaisons et groupe et une pluralité d'unités structurelles identiques sont liées, un nombre des unités structurelles est égal à 2 ou moins.
- Dérivé de lipide selon l'une quelconque des revendications 1à 6, dans lequel P est le polyéthylène glycol.
- Dérivé de lipide selon l'une quelconque des revendications 1à 6, dans lequel P est représenté par la formule (p1), la formule (p2), la formule (p3), la formule (p4), la formule (p5) ou la formule (p6)
dans les formules (p1) à (p6), m vaut de 1 à 6, X est un groupe hydrocarbure présentant de 1 à 7 atomes de carbone ou un groupe fonctionnel chimiquement réactif représenté par la formule (x1)
Y-Z3- (x 1)
dans la formule (x1), Y est un groupe carbonate actif ,
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2015193103 | 2015-09-30 | ||
PCT/JP2016/078886 WO2017057612A1 (fr) | 2015-09-30 | 2016-09-29 | Dérivé de lipide dans lequel des polymères hydrophiles sont liés par l'intermédiaire de lieurs de benzylidène-acétal cyclique |
Publications (3)
Publication Number | Publication Date |
---|---|
EP3357514A1 EP3357514A1 (fr) | 2018-08-08 |
EP3357514A4 EP3357514A4 (fr) | 2019-04-03 |
EP3357514B1 true EP3357514B1 (fr) | 2021-04-14 |
Family
ID=58427721
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP16851783.7A Active EP3357514B1 (fr) | 2015-09-30 | 2016-09-29 | Dérivé de lipide dans lequel un polymère hydrophile est lié par l'intermédiaire de lieurs de benzylidène-acétal cyclique |
Country Status (4)
Country | Link |
---|---|
US (1) | US10626217B2 (fr) |
EP (1) | EP3357514B1 (fr) |
JP (1) | JP6850417B2 (fr) |
WO (1) | WO2017057612A1 (fr) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR102546103B1 (ko) * | 2018-03-20 | 2023-06-21 | 니치유 가부시키가이샤 | 분기형 단분산 폴리에틸렌 글리콜, 중간체 및 그 제조 방법 |
CN109251865B (zh) * | 2018-09-30 | 2021-06-15 | 哈尔滨工业大学 | 一种小球藻细胞表面耗氧保护层的制备方法 |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3948946A (en) | 1971-10-26 | 1976-04-06 | Sandoz Ltd., (Sandoz Ag) | Cyclic acetals and mercaptals |
BE790493A (fr) | 1971-10-26 | 1973-04-24 | Sandoz Sa | Nouveaux composes heterocycliques utilisables comme stabilisants de matieres organiques et leur preparation |
JP2012509366A (ja) | 2008-11-17 | 2012-04-19 | エンゾン ファーマシューティカルズ,インコーポレーテッド | 核酸送達系のための放出可能ポリマー脂質 |
WO2012113571A1 (fr) | 2011-02-24 | 2012-08-30 | Ktb Tumorforschungsgesellschaft Mbh | Promédicaments à base de bisphosphonate |
CN105121506B (zh) | 2013-03-25 | 2017-03-08 | 日油株式会社 | 具有苯亚甲基缩醛连接基团的亲水性聚合物衍生物 |
JP6631827B2 (ja) | 2014-03-31 | 2020-01-15 | 日油株式会社 | 環状ベンジリデンアセタールリンカーを有する親水性ポリマー誘導体 |
JP6784932B2 (ja) | 2015-03-31 | 2020-11-18 | 日油株式会社 | 生体機能性分子または薬物キャリアの化学修飾用生分解性ポリエチレングリコール誘導体 |
-
2016
- 2016-09-29 EP EP16851783.7A patent/EP3357514B1/fr active Active
- 2016-09-29 WO PCT/JP2016/078886 patent/WO2017057612A1/fr active Application Filing
- 2016-09-29 JP JP2016190528A patent/JP6850417B2/ja active Active
- 2016-09-29 US US15/764,441 patent/US10626217B2/en active Active
Non-Patent Citations (1)
Title |
---|
None * |
Also Published As
Publication number | Publication date |
---|---|
EP3357514A4 (fr) | 2019-04-03 |
US20180312633A1 (en) | 2018-11-01 |
US10626217B2 (en) | 2020-04-21 |
EP3357514A1 (fr) | 2018-08-08 |
JP2017066397A (ja) | 2017-04-06 |
WO2017057612A1 (fr) | 2017-04-06 |
JP6850417B2 (ja) | 2021-03-31 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11530295B2 (en) | Hydrophilic polymer derivative having cyclic benzylidene acetal linker | |
US11529423B2 (en) | Biodegradable polyethylene glycol derivative having cyclic benzylidene acetal linker | |
US10633489B2 (en) | Hydrophilic polymer derivative having benzylidene acetal linker | |
EP2123304A1 (fr) | Composés utilisés en tant que nanotransporteurs et leur utilisation | |
EP3524631A1 (fr) | Polyéthylène glycol monodispersé de type hétéro ramifié, procédé de production et conjugué associés | |
EP3318591A1 (fr) | Polyéthylèneglycol monodispersé de type hétéro, intermédiaire pour la production de polyéthylèneglycol monodispersé de type hétéro, procédés pour leur préparation et conjugué de polyéthylèneglycol monodispersé de type hétéro | |
EP3357514B1 (fr) | Dérivé de lipide dans lequel un polymère hydrophile est lié par l'intermédiaire de lieurs de benzylidène-acétal cyclique | |
US9029568B2 (en) | Branched hetero polyfunctional polyoxyalkylene compound and intermediate thereof | |
EP3604383A1 (fr) | Procédé de production d'un dérivé de polyoxyéthylène ayant des groupes hydroxy au niveau d'une extrémité | |
US11905367B2 (en) | Branched monodispersed polyethylene glycol, intermediate and methods for producing same | |
EP3438155B1 (fr) | Hydrogel biodégradable présentant une structure cyclique de benzylidène acétal |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE |
|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE |
|
17P | Request for examination filed |
Effective date: 20180329 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |
|
AX | Request for extension of the european patent |
Extension state: BA ME |
|
DAV | Request for validation of the european patent (deleted) | ||
DAX | Request for extension of the european patent (deleted) | ||
A4 | Supplementary search report drawn up and despatched |
Effective date: 20190301 |
|
RIC1 | Information provided on ipc code assigned before grant |
Ipc: C08G 65/329 20060101ALI20190225BHEP Ipc: A61K 47/34 20170101AFI20190225BHEP Ipc: A61K 9/127 20060101ALI20190225BHEP Ipc: C07D 317/20 20060101ALI20190225BHEP |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: EXAMINATION IS IN PROGRESS |
|
17Q | First examination report despatched |
Effective date: 20200312 |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R079 Ref document number: 602016056237 Country of ref document: DE Free format text: PREVIOUS MAIN CLASS: A61K0047340000 Ipc: C07D0317200000 |
|
RIC1 | Information provided on ipc code assigned before grant |
Ipc: C07D 317/28 20060101ALI20200805BHEP Ipc: C07D 317/20 20060101AFI20200805BHEP Ipc: C07D 317/22 20060101ALI20200805BHEP Ipc: C07D 319/06 20060101ALI20200805BHEP Ipc: C07D 317/24 20060101ALI20200805BHEP Ipc: A61K 47/34 20170101ALI20200805BHEP Ipc: C07D 405/06 20060101ALI20200805BHEP Ipc: A61K 9/127 20060101ALI20200805BHEP Ipc: C07D 405/12 20060101ALI20200805BHEP Ipc: C08G 65/331 20060101ALI20200805BHEP |
|
GRAP | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOSNIGR1 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: GRANT OF PATENT IS INTENDED |
|
INTG | Intention to grant announced |
Effective date: 20200915 |
|
GRAJ | Information related to disapproval of communication of intention to grant by the applicant or resumption of examination proceedings by the epo deleted |
Free format text: ORIGINAL CODE: EPIDOSDIGR1 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: EXAMINATION IS IN PROGRESS |
|
GRAP | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOSNIGR1 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: GRANT OF PATENT IS INTENDED |
|
INTC | Intention to grant announced (deleted) | ||
INTG | Intention to grant announced |
Effective date: 20201222 |
|
GRAS | Grant fee paid |
Free format text: ORIGINAL CODE: EPIDOSNIGR3 |
|
GRAA | (expected) grant |
Free format text: ORIGINAL CODE: 0009210 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE PATENT HAS BEEN GRANTED |
|
AK | Designated contracting states |
Kind code of ref document: B1 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |
|
REG | Reference to a national code |
Ref country code: GB Ref legal event code: FG4D |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: EP |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: NV Representative=s name: BOVARD AG PATENT- UND MARKENANWAELTE, CH |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R096 Ref document number: 602016056237 Country of ref document: DE |
|
REG | Reference to a national code |
Ref country code: IE Ref legal event code: FG4D |
|
REG | Reference to a national code |
Ref country code: AT Ref legal event code: REF Ref document number: 1382279 Country of ref document: AT Kind code of ref document: T Effective date: 20210515 |
|
REG | Reference to a national code |
Ref country code: LT Ref legal event code: MG9D |
|
REG | Reference to a national code |
Ref country code: AT Ref legal event code: MK05 Ref document number: 1382279 Country of ref document: AT Kind code of ref document: T Effective date: 20210414 |
|
REG | Reference to a national code |
Ref country code: NL Ref legal event code: MP Effective date: 20210414 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: FI Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20210414 Ref country code: LT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20210414 Ref country code: HR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20210414 Ref country code: AT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20210414 Ref country code: BG Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20210714 Ref country code: NL Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20210414 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: IS Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20210814 Ref country code: LV Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20210414 Ref country code: GR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20210715 Ref country code: PL Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20210414 Ref country code: PT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20210816 Ref country code: NO Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20210714 Ref country code: SE Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20210414 Ref country code: RS Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20210414 |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R097 Ref document number: 602016056237 Country of ref document: DE |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: EE Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20210414 Ref country code: CZ Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20210414 Ref country code: DK Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20210414 Ref country code: ES Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20210414 Ref country code: RO Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20210414 Ref country code: SK Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20210414 Ref country code: SM Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20210414 |
|
PLBE | No opposition filed within time limit |
Free format text: ORIGINAL CODE: 0009261 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT |
|
26N | No opposition filed |
Effective date: 20220117 |
|
REG | Reference to a national code |
Ref country code: BE Ref legal event code: MM Effective date: 20210930 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: IS Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20210814 Ref country code: MC Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20210414 Ref country code: AL Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20210414 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LU Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20210929 Ref country code: IT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20210414 Ref country code: IE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20210929 Ref country code: BE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20210930 |
|
P01 | Opt-out of the competence of the unified patent court (upc) registered |
Effective date: 20230410 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: CY Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20210414 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: HU Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT; INVALID AB INITIO Effective date: 20160929 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: GB Payment date: 20230920 Year of fee payment: 8 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: FR Payment date: 20230928 Year of fee payment: 8 Ref country code: DE Payment date: 20230920 Year of fee payment: 8 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: CH Payment date: 20231001 Year of fee payment: 8 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: MK Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20210414 |